From the Departments of Cardiology and Medicine (Genetics) of
Children's Hospital, Harvard Medical School, Boston, Mass (P.D., M.R.V.,
D.W., A.H.B.); the Division of Pediatric Cardiology, Kosair-Children's
Hospital, University of Louisville (Ky) School of Medicine (J.V.); and the
Department of Cardiology at Beth Israel/Deaconess Medical Center, Harvard
Medical School, Boston, Mass (V.K.).
Correspondence to Alan H. Beggs, PhD, Genetics Division, Children's Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail beggs{at}rascal.med.harvard.edu
Background—Long-QT syndrome (LQTS)
is a disorder of ventricular repolarization characterized
by a prolonged QT interval, syncope, seizures, and sudden death.
Recently, three forms of LQTS have been shown to result from mutations
in potassium or sodium ion channel genes: KVLQT1 for
LQT1, HERG for LQT2, and SCN5A for LQT3.
IsK, an apparent potassium channel subunit encoded by
KCNE1 on chromosome 21, regulates both KVLQT1 and HERG.
This relationship makes KCNE1 a likely candidate gene,
because mutations of these genes are known to cause both the autosomal
dominant Romano-Ward and recessive Jervell and Lange-Nielsen (JLN)
forms of LQTS.
Methods and Results—We screened 84 unrelated patients with
Romano-Ward and 4 with JLN for possible mutations in
KCNE1. We identified one homozygous mutation in a JLN
patient that results in the nonconservative substitution of Asn for Asp
at amino acid 76. The patient is congenitally deaf-mute, with recurrent
syncopal events and a greatly prolonged QTc interval. The
proband's mother and half-sister are both heterozygous for this
mutation. Remarkably, both these family members have prolonged
QTc intervals and would have been classified as Romano-Ward
patients if not for the proband's diagnosis of JLN. This mutation was
not identified in more than 100 control individuals.
Conclusions—These data provide strong evidence that
KCNE1 mutations represent a fifth LQTS locus
(LQT5). Further functional analysis, as well as the
identification of more LQTS patients with KCNE1
mutations, will be important to confirm the role of IsK
in LQTS.
© 1998 American Heart Association, Inc.
Brief Rapid Communications
Mutation of the Gene for IsK Associated With Both Jervell and Lange-Nielsen and Romano-Ward Forms of Long-QT Syndrome
Key Words: arrhythmia • genes • molecular biology • long-QT syndrome • syncope
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